Generic Name

Voriconazole

Mechanism

• Inhibits CYP14A (sterol‑14α‑demethylase) – a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol.
• Disruption of ergosterol synthesis weakens fungal cell membrane integrity, leading to fungal cell death.
• Unlike first‑generation azoles, it exhibits broad activity against azole‑resistant strains and has a faster onset of action.

Pharmacokinetics

• Absorption – Oral bioavailability ~96 % (after a 200 mg maintenance dose). Oral bioavailability is reduced by ~10 % with high‑fat meals.
• Distribution – Volume of distribution ~42 L; penetrates well into tissues, cerebrospinal fluid, and lungs.
• Metabolism – Extensive hepatic metabolism via CYP2C19, CYP3A4, and CYP2C9.
• Elimination – Primarily renal (≈30 % unchanged).
• Half‑life – 12–20 h, depending on CYP2C19 phenotype.
• Drug interactions – Potentiates inhibition of CYP2C19 substrates; elevate serum concentrations of drugs like clopidogrel, phenytoin, and levothyroxine.
• Special populations – Dosage adjustments in severe hepatic impairment; caution in pregnancy (Category B).

Indications

• Invasive aspergillosis (including chronic pulmonary disease).
• Candidemia, esophageal candidiasis, and otomycosis when other azoles fail.
• Voriconazole prophylaxis in high‑risk neutropenic patients (e.g., AML induction).
• Empirical therapy for invasive fungal infections pending culture data.

Contraindications

• Absolute contraindication: Hypersensitivity to any component.
• Cautions:
• Severe hepatic dysfunction (ALT/AST > 5× ULN).
• Seizure disorders (may lower seizure threshold).
• Pregnancy: Consider fetal risk vs benefit.
• Concomitant CYP2C19 inhibitors (e.g., fluconazole) can precipitate toxicity.

Dosing

*Loading doses ensure therapeutic plasma levels > 1 µg/mL.
TDM is recommended to adjust for inter‑patient variability (see Monitoring).
Alternate dosing if renal/hepatic impairment or drug‑drug interactions are present.*

Adverse Effects

• Common
• Visual disturbances (blurred vision, photophobia).
• Rash, pruritus, or Stevens–Johnson syndrome.
• Elevated liver enzymes (ALT/AST, ↑ GGT).
• GI upset (nausea, vomiting).
• Serious
• Seizures (dose‑related).
• Hypersensitivity reactions (anaphylaxis).
• Hematologic toxicity (anemia, neutropenia).
• Visual hallucinations or vivid dreams.

Monitoring

• Baseline – CBC, CMP, LFTs, serum creatinine.
• During therapy –
• Liver function: ALT, AST, bilirubin (twice weekly first month, then monthly).
• Visual: Patient diary or formal ophthalmologic exam if symptoms arise.
• Therapeutic drug monitoring (TDM): Target trough 1–5 µg/mL; check after dosing change or at steady‑state (~2 weeks).
• Drug interactions: Review concurrent CYP2C19 inhibitors or substrates.

Clinical Pearls

• TDM saves lives – Voriconazole shows a *wide therapeutic index*; sub‑apeutic levels lead to relapse, while supratherapeutic levels precipitate neurotoxicity.
• CYP2C19 phenotype matters – Poor metabolizers have prolonged exposure; consider a *lower maintenance dose* (e.g., 4 mg/kg q12h).
• Avoid high‑fat meals before oral dosing – Reduces absorption slightly; patients should take the drug *on an empty stomach* or one hour before/after food.
• Step‑down strategy – Switch to oral after 7–14 days of IV therapy once the patient is clinically stable and plasma levels are adequate.
• Prophylaxis caution – In neutropenic prophylaxis, risk‑benefit must be weighed against potential for resistance and visual toxicity.
• Pregnancy & lactation – No robust data on infant safety; most clinicians err on the side of caution and prefer alternative treatments when feasible.

Reference: WHO Model List of Essential Medicines 2022; Sanford Guide to Antimicrobial Therapy; CLSI M59 guidelines for intravenous antifungal therapy.